Caroline Bell

Serotonin reuptake inhibitor withdrawal.

We studied reported withdrawal symptoms in a retrospective chart review of 352 patients treated in an outpatient clinic with the nonselective serotonin reuptake inhibitor clomipramine or with one of the selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine, paroxetine, or sertraline. In 171 patients who were supervised during medication tapering and discontinuation, the most common symptoms were dizziness, lethargy, paresthesia, nausea, vivid dreams, irritability, and lowered mood. When patients with at least one qualitatively new symptom were defined as cases, these symptoms occurred significantly more frequently in patients who had been treated either with one of the shorter half-life SSRIs, fluvoxamine or paroxetine (17.2%), or with clomipramine (30.8%), than in patients taking one of the SSRIs with longer half-life metabolites, sertraline or fluoxetine (1.5%). The rate was not significantly different between the different shorter half-life treatments. Cases treated with fluvoxamine or paroxetine had received a significantly longer period of treatment (median 28 weeks) than noncases (16 weeks), but there were no significant associations with age or with diagnostic grouping. There was a trend toward an association with male sex. The majority of cases occurred despite slowly tapered withdrawal. Symptoms persisted for up to 21 days (mean = 11.8 days) after onset. These symptoms were relieved within 24 hours by restarting the medication, but were not relieved by benzodiazepines or by moclobemide. A role has been suggested for serotonin in coordinating sensory and autonomic function with motor activity. We suggest that this may lead to useful hypotheses about the pathophysiology of withdrawal symptoms from serotonin reuptake inhibitors.

Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders.

Selective serotonin reuptake inhibitors (SSRIs) have demonstrated efficacy in depression and anxiety disorders. This raises the question of how the single action of serotonin reuptake inhibition can improve several psychiatric conditions. In order to understand this apparent paradox it is necessary to consider where SSRIs act in the pathogenic process underlying depression or anxiety disorders. Tryptophan depletion has been used extensively in research into depression and has shown that, in patients receiving an SSRI whose depression is in remission, depleting serotonin leads to recurrence of the disorder. Similar results have been found for panic disorder. This suggests that increased levels of serotonin are necessary in the synapse for the SSRI to be effective in the treatment of depression and panic disorder. In obsessive compulsive disorder, depletion of serotonin in patients recovered on an SSRI does not cause relapse; receptor adaptation may be more important. Variations within the SSRI drug class, such as the selectivity ratios for serotonin versus noradrenaline uptake, elimination half-life, and affinity for the 5-HT2 receptor have been identified and may be important determinants of efficacy, side effects and clinical use.

Correlation of subjective and objective sleep measurements at different stages of the treatment of depression

Studies of the correlation of subjective and objective sleep measures in depressed patients have produced mixed results so far. Further, they were carried out in sleep laboratories and tended to obtain one-off assessments, thus not taking into account the effect of treatment. We investigated forty (40) patients over the course of 8-week treatment of depression with either paroxetine or nefazodone. We used home polysomnography at baseline, nights 3 and 10, and week 8 of treatment, with extensive assessments of subjective sleep, the morning after each sleep recording. The patients were able to judge accurately their total sleep time and sleep onset latency, both before and during treatment. However, they were inaccurate in estimating the number of times they woke up during the night. Sleep satisfaction correlated negatively with Stage 1 sleep at baseline. Sleep quality was represented by a combination of subjective parameters measuring the ease of initiation and maintenance of sleep, and it appeared to derive from slow wave sleep and sleep continuity as seen in polysomnography. The partial discrepancy between subjective and objective measures suggests that a cognitive element is combined with the biological element to produce the sleep problems reported by depressed patients.

Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine

The neurobiological basis of panic disorder has not been clearly established, although a role for serotonin (5-HT) has been postulated. It is clear that drugs which increase 5-HT neurotransmission are effective in treating the condition but how they do so remains a point of debate. The aim of this study was to determine if lowering brain serotonin activity using the technique of tryptophan depletion provoked a short-term relapse of panic symptoms in patients with panic disorder who had responded to drug treatment. Fourteen patients with panic disorder who had responded to treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine received a tryptophan-free amino acid drink on one occasion and a control drink on the other in a double-blind crossover design. In addition, they received an infusion of flumazenil (used as a pharmacological challenge) and placebo on each day. The tryptophan depleted drink produced an 87% reduction in plasma tryptophan concentration. Flumazenil produced a panic attack (defined by changes in the panic inventory) in seven out of 14 patients when tryptophan depleted and one out of 14 on the control day (p < 0.02). Three patients also experienced temporary depressive symptoms when tryptophan depleted, with no mood changes being seen on the control days. We conclude that rapid lowering of brain serotonin function can allow the precipitation of panic symptoms in response to flumazenil in panic disorder patients who have responded to treatment with an SSRI. This implies that in panic disorder increased 5-HT availability is important in maintaining the response to SSRIs.

Tryptophan depletion reverses the therapeutic effect of selective serotonin reuptake inhibitors in social anxiety disorder

BACKGROUND Tryptophan depletion studies have suggested that central serotonin (5-hydroxytryptamine, 5-HT) function mediates the therapeutic effect of selective serotonin reuptake inhibitors (SSRIs) in depression and panic disorder. The present study tested the hypothesis that temporary reduction in central 5-HT transmission, through acute tryptophan depletion, could reverse the therapeutic effect of the SSRIs in social anxiety disorder (SAD) patients. METHODS Fourteen patients with SAD who showed sustained clinical improvement with SSRI treatment underwent tryptophan depletion in a double-blind, placebo-controlled, crossover design, over 2 days 1 week apart. At the peak time of depletion, the participants also underwent three behavioral challenges: autobiographical script, verbal task, and neutral script. Psychological outcome was assessed with the Spielberger State Anxiety Inventory (STAI) Form Y-1 and visual analog scales (VAS) measuring anxiety, depression, and somatic symptoms. RESULTS Anxiety was significantly increased on the depletion day compared with the control day, both on the STAI Form Y-1 and composite VAS score. Furthermore, there was a significant depletion x time interaction, explained mainly by the anxiogenic effect of the autobiographical script. In contrast, the verbal and the neutral tasks failed to differentiate between depletion and placebo. CONCLUSIONS Tryptophan depletion induced significant increase of anxiety in treated SAD patients, which was more prominent during the recital of an autobiographical script. This finding supports the notion that SSRIs improve social anxiety by increasing 5-HT availability. The autobiographical script seems to be a more robust challenge test for SAD than the stressful verbal task.

Adult night terrors and paroxetine

Although rare, night terrors are difficult to treat and a major management problem, especially when accompanied by sleepwalking or other automatic behaviours. Severe injury (sometimes death) during the period of confusion following the rise from bed has been reported, and more frequent attacks lead to serious disruption of sleep, which may impair subsequent daytime functioning and result in psychiatric comorbidity. Night terrors can thus cause severe disability, and effective therapy would be of benefit to patients and their families. There have been reports of treatment with benzodiazepines, imipramine, and longterm psychotherapy, but only benzodiazepines have shown any notable success. Selective serotonin reuptake inhibitors (SSRIs) have antipanic actions and there is some overlap in symptoms of nocturnal panic attacks and night terrors. We report a series of six patients with night terrors, referred for drug treatment because of distressing or dangerous accompanying behaviours, or sleep disruption. All six patients were assessed clinically and by home polysomnography (medilog). All responded to treatment with the SSRI paroxetine (table). In these patients paroxetine was effective in the treatment of longstanding and disabling night terrors and may be as effective as benzodiazepines, although formal comparison is necessary. Two of our patients were having terrors while on benzodiazepines, possibly because of the development of tolerance which does not occur with paroxetine. Other advantages of paroxetine over benzodiazepines is that it treats comorbid or secondary depression and is not a drug of abuse. We suggest that the terror-suppressing action of paroxetine is a direct effect of its ability to increase 5hydroxytryptamine (5-HT) concentrations in the brainstem by blocking reuptake. Terror-like behaviour in animals and man can be readily provoked by stimulation of the periaqueductal grey matter, and this behaviour in animals is suppressed by acute administration of SSRIs and direct-acting 5HT2c receptor agonists. 5HT2c agonists are in clinical development for the treatment of anxiety and depression and it would be interesting to test their efficacy in night terrors. The effects of paroxetine on sleep are known and probably do not contribute to its effect on night terrors. Further evidence that the therapeutic action of paroxetine may be direct rather than through a neuroadaptive mechanism (thought to underlie the antipanic action) comes from the patients who had relapse after stopping treatment. Night terrors recurred rapidly as plasma and brain concentrations of paroxetine fell, and restarting treatment quickly suppressed them again. In one patient the treatment effect seemed dose related. The two cases previously reported to have responded to imipramine also responded rapidly, suggesting a different mode of action to the antidepressant effect. Imipramine also has 5-HT-uptake blocking effects. We found paroxetine to be a safe and effective treatment for disabling night terrors in a small group of patients. The effectiveness of such a selective agent as paroxetine may also suggest a role for decreased central 5-HT function in the aetiology of night terrors.

The neurobiology of social phobia.

Abstract Although Social Phobia has been recognised for centuries in comparison with other anxiety disorders, relatively little work has been done to understand its neural basis. The present review attempts to redress this balance by giving an overview of the current state of knowledge in this disorder. By putting together data from the treatment responses to specific agents, the effects of chemical challenges which have been used in other anxiety disorders and by reviewing data on central and peripheral neurotransmitter and endochrine abnormalities, it is possible to begin to generate some potentially testable therories of aetiology and mechanisms. Finally, we review the potential use of neuroimaging techniques to better detail the brain circuits and possibly neurotransmitters involved in social phobia, showing some of our preliminary work using 15O water blood flow PET activation studies to determine the brain circuits in which metabolism is changed during the experience of social anxiety.

Depleting Serotonin Enhances both Cardiovascular and Psychological Stress Reactivity in Recovered Patients with Anxiety Disorders

Abstract: Serotonin-promoting drugs show cardioprotective properties in patients with anxiety or depression, but it is not known if this is a direct effect of increasing serotonin. We aimed to characterize the effect of serotonin manipulation through acute tryptophan depletion on cardiovascular and psychological responses to stress challenge in recovered patients with anxiety disorders. In 27 recovered patients with anxiety disorders (panic disorder treated by selective serotonin reuptake inhibitors (SSRIs) or cognitive behavioral therapy, social anxiety disorder treated by SSRIs), we performed a double-blind randomized crossover study. On 2 separate days, the subjects ingested an acute tryptophan-depleting (aTD) or nondepleting (nD) drink in random order and underwent a stress challenge at time of maximum depletion. Systolic blood pressure (P = 0.007; diff = 9.0 mm Hg; 95% confidence interval (CI), 2.6-15.3 mm Hg) and diastolic blood pressure (P = 0.032; diff = 5.7 mm Hg; 95% CI, 0.6-10.9 mm Hg) responses to stress were significantly greater under aTD than nD, as were the psychological responses to stress (for Spielberger state anxiety, difference in stress response between aTD and nD = 7.11; P = 0.025). Blood pressure responses to stress showed no correlation with psychological responses. The significant increases in acute stress sensitivity in both cardiovascular and psychological domains on serotonin depletion suggest that serotonin is involved in the control of both cardiovascular and psychological aspects of the acute stress response. The lack of correlation in the difference between aTD and nD conditions in cardiovascular and psychological responses suggests that serotonin may have distinct effects on these 2 domains, rather than the cardiovascular responses being merely a secondary consequence of psychological changes.

Increased sympathetic response to standing in panic disorder

Although autonomic function has been investigated in panic disorder (PD), previous studies have not used non-invasive beat by beat blood pressure (BP) monitoring to assess the rapid dynamics of BP during autonomic reflex tests. The hypothesis of the current study was that patients with PD would show increased cardiovascular sympathetic reactivity compared with healthy or anxious controls, as assessed by the initial overshoot of diastolic BP during the immediate response to standing. Patients with PD (n=56), social phobia (n=28) and healthy volunteers (n=56) were tested using finger photoplethysmography during an orthostatic challenge. Panic disorder patients showed an increased BP overshoot compared with both control groups. Moreover, in a preliminary assessment of selective serotonin reuptake inhibitor treatment effects, the BP overshoot was significantly reduced towards normal values. These findings are consistent with recent evidence for increased sympathetic baroreflex function in PD and may be relevant to the pathophysiology of the disorder.

Plasma oxytocin levels in depression and their correlation with the temperament dimension of reward dependence

Evidence suggests that the neuropeptide oxytocin plays a role in social affiliation. This behaviour may be related more to personality dimensions than specific psychiatric diagnoses. This study investigated the relationship between plasma oxytocin levels and personality dimensions using the Temperament and Character Inventory (TCI) in 60 outpatients with major depression. The strongest correlation was between plasma oxytocin levels and the temperament dimension of Reward Dependence (0.425 Pearson correlation). This suggested that 17% of the variance in plasma oxytocin levels was explained by the Reward Dependence scores. There was a significant positive correlation between plasma oxytocin levels and the Reward Dependence personality dimension